Immune-Mediated Hemolytic Anemia and Thrombocytopenia in Clonal B-Cell Disorders: A Review Urshila Durani, MD, MPH, Ronald S. Go, MD, and Neil E. Kay, MD The authors are affiliated with the Abstract: Autoimmune hemolytic anemia (AIHA) and immune Division of Hematology in the Depart- thrombocytopenia purpura (ITP) have been associated with B-cell ment of Medicine at the Mayo Clinic lymphoproliferative disorders. Here, we review the epidemiology, in Rochester, Minnesota. Dr Durani pathogenesis, diagnosis, and treatment of these autoimmune disor- is a fellow, Dr Go is an associate ders, specifically in the setting of B-cell malignancies. AIHA and ITP professor of medicine, and Dr Kay is a professor of medicine. are classically associated with chronic lymphocytic leukemia (CLL) but have also been reported in plasmacytic and lymphoprolifera- tive disorders. AIHA includes both warm AIHA and cold agglutinin Corresponding author: disease, the latter of which is strongly associated with Walden- Neil E. Kay, MD ström macroglobulinemia. The pathogenesis of these cytopenias Mayo Clinic varies with the underlying disease, but malignant cells serving as 200 First St SW Rochester, MN 55905 antigen-presenting cells to T lymphocytes, with the generation of Tel: (507) 284-2511 autoreactive lymphocytes, may be involved. The diagnosis requires E-mail: [email protected] the presence of hemolysis and a positive direct antiglobulin test result. In a minority of cases, the direct antiglobulin test result is negative, and more specialized testing may be required. Data on the prognostic effect of these comorbidities are conflicting, and the prognosis may vary depending on when in the B-cell malignant process the cytopenia(s) develops. The treatment of AIHA and ITP in the setting of B-cell lymphoproliferative disorders often involves treatment of the underlying disorder, although in some cases of CLL, treatment of the underlying disorder is not indicated, and management is similar to that for idiopathic AIHA or ITP. Introduction Autoimmune cytopenias are uncommon but well-recognized complications of clonal B-cell disorders.1 Specifically, autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia purpura (ITP) are more frequently seen than other cytopenias. The diagnosis Keywords of these disorders is complicated, and the causal mechanism(s) of Autoimmune, chronic lymphocytic leukemias, the association between the malignant disorders and the cytopenias hemolytic anemia, lymphoma, multiple myeloma, is not completely understood, although several theories have been thrombocytopenia proposed. This review discusses the epidemiology and pathophysiol- 670 Clinical Advances in Hematology & Oncology Volume 16, Issue 10 October 2018 AIHA AND ITP IN CLONAL B-CELL DISORDERS ogy of these comorbidities, their prognostic significance, patients, prompting the authors to propose, perhaps pre- and current options for diagnosis and treatment. maturely, that a diagnosis of LGL leukemia be entertained in any patient with ITP.19 On the other hand, Hodgkin Epidemiology lymphoma is rarely associated with autoimmune hema- tologic complications. In one large retrospective study Although autoimmune cytopenias have been appreciated of 1029 patients with approximately 6600 person-years in every type of B-cell clonal disorder, they are classically of follow-up, AIHA or ITP was diagnosed in only 12 and commonly associated with B-chronic lymphocytic patients (1.2%; 5 at presentation, 7 during follow-up).20 leukemia (CLL).2-4 AIHA has been observed in anywhere Although one prospective study conducted in India from 4% to 25% of CLL cohorts in various studies.2,3,5-7 found that severe AIHA developed in 10% of patients with However, Zent and colleagues8 point out that many of multiple myeloma during the course of their disease,21 the studies describing the cumulative risk for AIHA in plasmacytic disorders, as opposed to lymphoprolifera- CLL were conducted in tertiary care centers, with rela- tive disorders, generally do not have a strong association tively small cohorts and an inherent bias toward advanced with autoimmune cytopenias. However, one retrospective malignant disease. Newer studies, which have included study did find a high rate of monoclonal gammopathy of larger, population-based cohorts and used more accurate undetermined significance (16.5%) in patients older than diagnostic methods, consistently demonstrate a risk of 50 years with warm AIHA and no preceding lympho- 3% to 10%.5,9 ITP occurs less commonly, in fewer than plasmacytic malignancy.22 In addition, AIHA has been 5% of cases. Interestingly, the prevalence of a positive reported in up to 20% of patients and cold agglutinin direct antiglobulin test (DAT) result seems to increase in disease (CAD) in up to 10% of patients with Walden- patients with later-stage disease; however, clinical AIHA ström macroglobulinemia (WM) or lymphoplasmacytic develops in only a subset of these patients.9 A universal lymphoma.23 CAD is serologically characterized as a cold- and uniform characterization of the epidemiology of reactive immunoglobulin M (IgM)–mediated process, as AIHA and ITP in CLL is difficult because these disorders opposed to the usual warm IgG-associated AIHA seen in have been attributed to both the underlying disease and other lymphoproliferative disorders. ITP also occurs less certain treatments, such as purine nucleoside analogues.10 often (<5% of patients) in WM.23,24 Autoimmune hematologic complications occur less commonly in malignant hematologic disorders other than Pathophysiology CLL. AIHA has been described in 1% to 6% of patients with lymphoma in retrospective studies, whereas ITP is Proposed models for the development of autoimmune seen in fewer than 1%.11 A single-institution retrospective cytopenias in B-cell disorders differ according to the analysis of 637 patients with lymphoproliferative disease, underlying malignancy. The pathogenesis of autoimmune published in 1987, found that 15 patients (2.4%) either cytopenia has been well studied in CLL. In AIHA in this presented with or acquired AIHA during the course of disorder, polyclonal warm IgG antibodies produced by their disease.12 Evans syndrome was diagnosed in 2 of nonmalignant B cells have been found to be the culprit these patients, and lupus with AIHA developed in 1 antibodies.2,3 What, then, is the role of the malignant CLL patient. ITP developed in 4 additional patients (0.6%). B cell in the predisposition to autoimmunity? One theory AIHA was the most commonly seen autoimmune entity is that the leukemia cell acts as an antigen-presenting in this series. A more recent study, published in 2002, cell to induce a T-cell response to red blood cell (RBC) found only 1 case of AIHA in the records of 421 patients antigens, which in turn stimulates IgG antibody produc- with non-Hodgkin lymphoma (NHL) that spanned 20 tion by normal B cells.25 B-cell receptors, which serve as years.13 This variability in prevalence of AIHA is likely the point of contact between antigens and the leukemic due to differences in the histologic subtype and biology cells, have been strongly implicated in the pathogenic of the lymphomas studied by each institution. The cumu- process, from antigen presentation to autoimmunity. One lative incidence of AIHA was higher in marginal zone study showed that the B-cell receptors (BCRs) found in lymphoma, a low-grade lymphoproliferative disorder approximately one-third of all cases of CLL are highly (10% in one study)14 and in T-cell lymphomas, especially restricted to a handful of stereotyped configurations.26 angioimmunoblastic T-cell lymphoma (8%-15%), than Subsequently, Maura and colleagues demonstrated that in other lymphomas.11,15-18 Large granular lymphocytic AIHA is more likely to develop in patients with certain (LGL) leukemia is another low-grade lymphoproliferative preserved BCR configurations.25 These studies suggest disorder that is often preceded by a variety of autoim- that a specific BCR subset in CLL may correlate with a mune disorders, most commonly ITP. In one retrospec- specific array of antigen reactivity, including autoreactiv- tive study, ITP preceded LGL leukemia in 59% of the ity.27-29 The BCR subsets can contribute to both disease Clinical Advances in Hematology & Oncology Volume 16, Issue 10 October 2018 671 DURANI ET AL aggressiveness and a pattern of autoimmunity in CLL.28,29 cated in CAD.45 The IgM identified can be polyclonal Another possible clue to the pathophysiology of (often postinfectious) or monoclonal.45,46 Monoclonal autoimmunity in CLL is that an adverse prognostic factor, IgM CAD can be associated with an underlying lym- unmutated immunoglobulin heavy chain variable region phoproliferative disease, such as WM, or can exist on its gene (IGHV) status, is more common in patients who own. In one population-based study, monoclonal IgM have CLL with AIHA than in those without AIHA.30 In was identified in 90% of cases, with kappa light chains one particular study, despite the well-established negative in 94%.47 Of the patients with available bone marrow prognostic significance of unmutated IGHV status, over- histology, 76% had features of a B-cell lymphoma and all survival did not differ significantly between patients 50% specifically had a lymphoplasmacytic lymphoma; with and those without AIHA (70% vs 80%; P>.05).30 in addition, a monoclonal band was identified on serum Unmutated IGHV, along with ZAP-70 positivity, has electrophoresis in 94% of the patients.47 These findings also been shown to correlate with the development of suggest that most cases of CAD may be secondary to an ITP and Evans syndrome.31-37 In addition, other adverse underlying malignant B-cell disorder, and so the pres- cytogenetic predictors, such as 11q or 17p deletion, were ence of CAD should raise that suspicion. In this case, associated with AIHA.25 A key question arising from the hemolysis is directly driven by malignant B cells these observations is why unmutated IGHV BCR con- producing IgM antibodies against certain erythrocyte figurations would lead to an increased risk for AIHA or antigens.